Internally generated circadian rhythms are reset each day by external cues to maintain a 24 h cycle. Phase shift responses often depend on circadian phase, which can be described in a phase-response curve (PRC). While light is associated with one PRC (the photic or LPRC), other stimuli produce a different, non-photic PRC (the non-photic or DPRC). The physiological events associated with these behaviorally expressed phase-shifting patterns are not well understood. The mammalian circadian pacemaker is located in the hypothalamic suprachiasmatic nuclei. Suprachiasmatic nuclei cells maintain a self-sustained oscillation in vitro, allowing measures of phase-shifting behavior from an isolated clock. Circadian clock phase shifting is measured in vitro by sampling spontaneous activity from suprachiasmatic neurons in the brain slice preparation following application of phase-shifting stimuli. This in vitro model of the circadian clock can be used to study effects of photic and non-photic phase-shifting agents. Glutamate and neuropeptide Y will be used as photic and non-photic agents, respectively. The proposed studies will uncover mechanisms mediating photic and non-photic phase shifting. Specific questions include: 1. What are the effects of neuropeptide Y on suprachiasmatic nuclei neurons? 2. What are the similarities and differences between photic and non-photic phase shifts? 3. At what point do photic and non-photic phase-shifting pathways interact? Disturbances in the phasing of circadian rhythms may underlie discomforts associated with jet lag and shift work, as well as various depressive disorders. Circadian rhythms underlie many important medical events and circadian timing of treatments has been profitably applied in chemotherapy cancer treatment. Greater knowledge of the intrinsic organization and the phase resetting properties of the mammalian circadian system will aid in further clinical applications of chronobiology.